Macrocyclic Peptides as Drug Candidates: Recent Progress and Remaining Challenges

Abstract

Peptides as a therapeutic modality attract much attention due to their synthetic accessibility, high degree of specific binding, and the ability to target protein surfaces traditionally considered “undruggable”. Unfortunately, at the same time, other pharmacological properties of a generic peptide, such as metabolic stability and cell permeability, are quite poor, which limits the success of de novo discovered biologically active peptides as drug candidates. Here, we review how macrocyclization as well as the incorporation of nonproteogenic amino acids and various conjugation strategies may be utilized to improve on these characteristics to create better drug candidates. We analyze recent progress and remaining challenges in improving individual pharmacological properties of bioactive peptides, and offer our opinion on interfacing these, often conflicting, considerations, to create balanced drug candidates as a potential way to make further progress in this area.

CyClick Chemistry for the Synthesis of Cyclic Peptides

“…Cyclic peptides have recently received considerable attention in the pharmaceutical industry because of their high stability, cell permeability, and enhanced potency as compared to their linear counterparts . Currently, more than 40 cyclic peptides are used as pharmaceuticals, and most of them are obtained from nature . The major driving force for the growing interest in cyclic peptides is due to their ability to interrupt protein–protein interactions (PPIs) in a highly specific manner .…”

“…[1][2][3][4][5] Currently,m ore than 40 cyclic peptides are used as pharmaceuticals,and most of them are obtained from nature. [6][7][8] Themajor driving force for the growing interest in cyclic peptides is due to their ability to interrupt protein-protein interactions (PPIs) in ah ighly specific manner. [9][10][11] Despite their importance,l aboratory synthesis of cyclic peptides can be challenging.A mong the most challenging cyclizations are those attempted on linear peptides containing less than seven amino acid residues.…”

Macrocyclization of an all-D linear peptide improves target affinity and imparts cellular activity: A novel stapled α-helical peptide modality

“…Combining d PMI-δ(1-5) and d PMI-δ(5-12) resulted in a stitched peptide, d PMI-δ (1,5,12), with the common attachment point for the two staples localised at residue 5 [ Figure 8]. As expected the CD spectra of the stitched d PMI-δ (1,5,12) showed increased helicity (52% helicity, Table 2). This agrees with reports on other peptides showing that the stitched and double stapled peptides often display increased helicity compared to the single stapled peptides [38, 39, 40 , 60-64].…”

“…We introduced an addition staple between positions 9 and 12 (i+3) in d PMI-δ (1)(2)(3)(4)(5) resulting in a d PMI-δ(1-5,9-12) double stapled peptide [ Figure 8]. Combining d PMI-δ(1-5) and d PMI-δ(5-12) resulted in a stitched peptide, d PMI-δ (1,5,12), with the common attachment point for the two staples localised at residue 5 [ Figure 8]. As expected the CD spectra of the stitched d PMI-δ (1,5,12) showed increased helicity (52% helicity, Table 2).…”

“…However, for intracellular targets, the peptide modality may be challenging due to proteolytic sensitivity, low conformational stability (yielding weak affinities and off-target effects), and poor cell permeability (further limiting engagement of intracellular targets and/or oral bioavailability) [5][6][7][8][9][10][11]. To address these issues, several strategies have been pursued, including macrocyclization and modifications of the peptide backbone to yield molecules with improved biological activities and pharmacokinetic properties as well as constraining the peptide into its biologically-relevant conformation that binds its target [5][6][7][8][9][10][11][12][13]. First, by constraining the peptides toward their bound conformations, entropic penalties upon binding are reduced, thus improving binding constants as well as potentially decreasing the opportunity for unwanted off-target effects.…”